Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[C:11]([CH3:18])=[N:12][C:13]([CH3:17])=[CH:14][C:15]=2[CH3:16])[C:3]=1[N+:19]([O-:21])=[O:20].C([NH:24][CH2:25][CH2:26][CH3:27])C.[CH2:28]1COC[CH2:29]1>>[CH2:28]([CH:25]([NH:24][C:2]1[C:3]([N+:19]([O-:21])=[O:20])=[C:4]([NH:9][C:10]2[C:11]([CH3:18])=[N:12][C:13]([CH3:17])=[CH:14][C:15]=2[CH3:16])[N:5]=[C:6]([CH3:8])[N:7]=1)[CH2:26][CH3:27])[CH3:29]
Reactant: C1CCOC1
Reactant: CCCNCC
Reactant: Cc1cc(C)c(Nc2nc(C)nc(Cl)c2[N+](=O)[O-])c(C)n1
Product: CCC(CC)Nc1nc(C)nc(Nc2c(C)cc(C)nc2C)c1[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
To a cooled solution of (6-chloro-2-methyl-5-nitro-pyrimidin-4-yl(2,4,6-trimethyl-pyridin-3-yl)-amine (88 mg, 0.29 mmol) in 1 ml of dry THF was added 1 ethyl-propyl-amine (80 mg, 0.92 mmol) at −78° C. The mixture was stirred at that temperature for 3 hrs, then warmed to −10° C. for 1 hour. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give the title compound (88 mg, 86%) as an orange solid, mp 151-152° C. 1H NMR (CDCl3) δ 9.16 (d, 1H), 6.92 (s, 1H), 4.35 (m, 1H), 2.50 (s, 3H), 2.39 (s, 3H), 2.18 (s, 3H), 2.16 (s, 3H), 1.5-1.80 (m, 4H), 0.94 (t, 6H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([C:14]2[C:19]([CH2:20][NH:21][CH2:22][CH3:23])=[CH:18][C:17]([CH3:24])=[CH:16][N:15]=2)[CH:7]=1)[CH3:2].FC(F)(F)C([O-])=O.[CH2:33]([N:40]=[C:41]=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([C:14]2[C:19]([CH2:20][N:21]([CH2:22][CH3:23])[C:41]([NH:40][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:42])=[CH:18][C:17]([CH3:24])=[CH:16][N:15]=2)[CH:7]=1)[CH3:2]
Reactant: CCNCc1cc(C)cnc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: O=C=NCc1ccccc1
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(OC)c(-c2ncc(C)cc2CN(CC)C(=O)NCc2ccccc2)c1

Procedure:
[3-(3-Ethylaminomethyl-5-methyl-pyridin-2-yl)-4-methoxy-phenyl]-acetic acid ethyl ester, trifluoroacetate (0.36 mmol) was reacted with benzyl isocyanate (0.05 mL, 0.44 mmol) and triethylamine (0.152 mL, 1.09 mmol) in CH2Cl2 to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:43])[NH:10][C:11]1[N:16]=[C:15]([CH2:17][OH:18])[C:14]2[C:19]([O:41][CH3:42])=[N:20][N:21]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13]=2[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.CN(C=O)C.[C:54]([Si:58]([CH3:61])([CH3:60])Cl)([CH3:57])([CH3:56])[CH3:55]>C(OCC)(=O)C>[CH2:1]([O:8][C:9](=[O:43])[NH:10][C:11]1[N:16]=[C:15]([CH2:17][O:18][Si:58]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:61])[CH3:60])[C:14]2[C:19]([O:41][CH3:42])=[N:20][N:21]([C:22]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:13]=2[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)OCc3ccccc3)nc(CO)c12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)OCc3ccccc3)nc(CO[Si](C)(C)C(C)(C)C)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
To a 50 mL round bottom flask charged with benzyl(4-(hydroxymethyl)-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)carbamate (180 mg, 0.315 mmol), imidazole (42.9 mg, 0.631 mmol) and DMF (3 ml) was added tert-butyldimethylchlorosilane (57.1 mg, 0.379 mmol). The flask was capped and the contents stirred at room temperature for 2 h. LCMS analysis indicated 80% conversion to the desire product. Excess tert-butyldimethylchlorosilane (25 mg) was added, and the reaction mixture stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate (20 mL), washed with water (2×30 mL), dried (MgSO4) and filtered. The solvent was evaporated under reduced pressure to afford crude benzyl(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)carbamate (199 mg, 0.291 mmol, 92% yield) as a colorless oil. MS: [M+H]+ m/z 685.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([NH2:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.O.Cl.[NH:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.[OH-].[K+]>CO>[NH:15]1[CH2:16][CH:17]=[C:18]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[C:6]([C:10]([NH2:12])=[O:11])[CH:5]=3)[NH:1][CH:2]=2)[CH2:19][CH2:20]1
Reactant: NC(=O)c1ccc2[nH]ccc2c1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NC(=O)c1ccc2[nH]cc(C3=CCNCC3)c2c1
Yield: 40.6 %

Procedure:
A mixture of 1H-indole-5-carboxamide (1.8 g), 4-piperidone hydrochloride monohydrate (3.4 g), and potassium hydroxide (11 g) in methanol (100 ml) was heated at reflux for 16 h. The mixture was cooled, and partitioned between ethyl acetate (200 ml) and saturated potassium carbonate (200 ml). The aqueous phase was separated, and extracted with ethyl acetate (100 ml. The organic extracts were combined, dried and the solvent evaporated in vacuo to give a semi-solid which was triturated with absolute ethanol (10 ml), and washed with ether (3×20 ml). The resultant solid was dried in vacuo to give the title compound, (1.1 g) m.p. 225°-230°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH:5]2[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:31]=[CH:32][CH:33]=2)O1>C(OCC)(=O)C.CCCCCC>[Cl:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[O:12][CH:5]1[C:4]2[C:9](=[N:10][CH:11]=[C:2]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([N:34]4[CH2:35][CH2:36][O:37][CH2:38][CH2:39]4)[CH:29]=3)[CH:3]=2)[NH:8][CH2:7][CH2:6]1
Reactant: Clc1cccc(OC2CCNc3ncc(Br)cc32)c1
Reactant: CC1(C)OB(c2cccc(N3CCOCC3)c2)OC1(C)C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Clc1cccc(OC2CCNc3ncc(-c4cccc(N5CCOCC5)c4)cc32)c1
Yield: 49 %

Procedure:
6-Bromo-4-(3-chlorophenoxy)-1,2,3,4-tetrahydro-[1,8]naphthyridine (20 mg) was reacted with 4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]morpholine (23.9 mg) as in General Procedure 13. Silica gel chromatography using a gradient of 0-100% ethyl acetate/hexane as the eluting solvent gave the title compound as a yellow foam (49% yield). LCMS: m/z=422.18 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.00-2.11 (m, 1H), 2.22-2.26 (m, 1H), 3.19 (t, J=4.8 Hz, 4H), 3.40-3.45 (m, 1H), 3.58-3.64 (m, 1H), 3.88 (t, J=4.8 Hz, 4H), 5.14 (bs, 1H), 5.37 (t, J=1.0 Hz, 1H), 6.82-6.92 (m, 2H), 6.92 (s, 1H), 6.95-7.02 (m, 2H), 7.03-7.08 (m, 1H), 7.20-7.33 (m, 2H), 7.55 (d, J=1.9 Hz, 1H), 8.27 (d, J=2.1 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[C:12](N1C=CN=C1)([N:14]1C=CN=[CH:15]1)=O.C(N(CC)CC)C.Cl.CNC>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:14]([CH3:15])[CH3:12])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)Cc1ccc(Br)cc1
Reaction time: 1 h
Yield: 63.4 %

Procedure:
A solution of 4-bromophenylacetic acid (960 mg, 4.49 mmol) in dichloromethane (30 ml) was treated in one portion with solid 1,1′-carbonyldiimidazole (730 mg, 4.5 mmol) at 20° C. with stirring under argon. This mixture was allowed to stir at room temperature for 15 minutes. Triethylamine (0.63 ml) was then added followed by dimethylamine hydrochloride (367 mg, 4.5 mmol) and the stirring continued for 1 hour. Most of the solvent was removed under reduced pressure and the residue added to a 20 g isolute silica sep-pak column and eluted from 0-50% ethyl acetate in petroleum ether to give the title compound as a colourless solid (689 mg, 64%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CN(C)CCCN=C=NCC.N1(C2N=C(CC(=O)N3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:35]4([CH2:43][CH2:42]4)C3)NC(=O)C=2)CCOCC1.[N:46]1([C:52]2[N:53]=[C:54]([CH2:59][C:60]([O-:62])=O)[NH:55][C:56](=[O:58])[CH:57]=2)[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1.[Na+]>CN(C)C=O>[N:46]1([C:52]2[N:53]=[C:54]([CH2:59][C:60](=[O:62])[N:1]3[C:3]4[C:4](=[C:35]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[CH:42]=[CH:43][CH:2]=4)[CH2:5][CH2:6]3)[NH:55][C:56](=[O:58])[CH:57]=2)[CH2:47][CH2:48][O:49][CH2:50][CH2:51]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CC2(CC2)c2ccccc21
Reactant: c1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2c(-c3ccccc3)cccc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
0.16 ml of pyridine, 240 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 210 mg of 4-phenyl-2,3-dihydro-1H-indole (reference example 1d) are successively added to a suspension of 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (example 1d, step 2d) in 5 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 15 hours, and is then concentrated to dryness under reduced pressure. The residue is taken up in and triturated from 30 ml of water, and then the precipitate formed is filtered off and then solubilized in a 90/10 dichloromethane/methanol mixture and, finally, concentrated to dryness under reduced pressure. The residue is purified by chromatography on a 30 g column of 20-45 μm silica, elution being carried out with a mixture of dichloromethane and methanol (90/10: v/v). The fractions containing the expected product are concentrated to dryness under reduced pressure and the residue is triturated from 20 ml of diisopropyl ether. The solid obtained is filtered off and then dried under reduced pressure at 40° C. 232 mg of 6-(morpholin-4-yl)-2-[2-oxo-2-(4-phenyl-2,3-dihydro-1H-indol-1-yl)ethyl]pyrimidin-4(3H)-one are thus obtained in the form of a pink solid, the characteristics of which are the following:
Reaction SMILES: [C:1]([N:9]1[CH2:12][C:11]2([CH2:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[C:17](/[CH:23]=[CH:24]/[C:25](O)=[O:26])[CH:18]=3)[O:13]2)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:42][O:43][CH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][O:45]1>C(Cl)Cl>[C:1]([N:9]1[CH2:12][C:11]2([CH2:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[C:17](/[CH:23]=[CH:24]/[C:25]([NH:42][O:43][CH:44]4[CH2:49][CH2:48][CH2:47][CH2:46][O:45]4)=[O:26])[CH:18]=3)[O:13]2)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NOC1CCCCO1
Reactant: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(C(=O)c3ccccc3)C1)O2
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CN(C(=O)c3ccccc3)C1)O2)NOC1CCCCO1
Yield: 51.9 %

Procedure:
A suspension of (E)-3-[1′-benzoyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid (200 mg, 0.50 mmol) in DCM (5 ml) was treated with TEA (0.11 ml, 0.82 mmol) and then with EDC (158 mg, 0.827 mmol), HOBt (107 mg, 0.793 mmol) and NH2OTHP (74 mg, 0.63 mmol) following the procedure described in Example 30, Step B, giving (E)-3-[1′-benzoyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (120 mg) as a light yellow solid.
Reaction SMILES: [CH3:1][N:2]1[N:6]=[C:5]([NH:7][C:8]2[CH:13]=[C:12]([Cl:14])[C:11]([Cl:15])=[CH:10][C:9]=2[N+:16]([O-])=O)[C:4]([C:19]#[N:20])=[N:3]1>C(O)C.Cl>[ClH:14].[NH2:20][C:19]1[C:4]2[C:5](=[N:6][N:2]([CH3:1])[N:3]=2)[NH:7][C:8]2[CH:13]=[C:12]([Cl:14])[C:11]([Cl:15])=[CH:10][C:9]=2[N:16]=1
Reactant: Cn1nc(C#N)c(Nc2cc(Cl)c(Cl)cc2[N+](=O)[O-])n1
Agent: Cl
Solvent: CCO
Product: Cn1nc2c(n1)C(N)=Nc1cc(Cl)c(Cl)cc1N2

Procedure:
To a slurry of 2-methyl-4[4,5-dichloro-2-nitroanilino]-1,2,3-triazole-5-carbonitrile (1.1 g) in ethanol (10 ml) was added anhydrous stannous chloride (2.0 g) in concentrated hydrochloric acid (10 ml) and the solution heated at reflux for one hour, cooled and the resulting solid filtered and dried at 70° C. under reduced pressure to give an orange crystalline solid, recrystallised from ethanol, melting point >255° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([NH:10][C:11]2[S:12][C:13]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[O:9])[CH:5]=[CH:4][N:3]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.O>CN1C(=O)CCC1>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:14]1[N:15]=[C:11]([NH:10][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:31]3[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]3)[CH:7]=2)=[O:9])[S:12][C:13]=1[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)c1ccnc(Cl)c1
Reactant: CN1CCNCC1
Solvent: O
Solvent: CN1CCCC1=O
Product: CN1CCN(c2cc(C(=O)Nc3nc(-c4ccco4)c(N4CCOCC4)s3)ccn2)CC1
Temperature: 150 °C
Reaction time: 8 h
Yield: 4.9 %

Procedure:
Compound 39 (391 mg, 1.00 mmol) was dissolved in NMP (10 mL), and 1-methylpiperazine (1.11 mL, 10.0 mmol) was added thereto, followed by stirring overnight at 150° C. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=19:1) to afford the entitled Compound 41 (22.2 mg, 5%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-])=O.[C:12]1([NH:18][C:19](=O)[CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[N:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:19]([CH3:20])=[N:9][C:3]=2[CH:4]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1Br
Reactant: CC(=O)Nc1ccccc1
Product: Cc1nc2cc(F)ccc2n1-c1ccccc1
Yield: 61 %

Procedure:
The title compound was prepared with the analogous procedure described in example 3 using 1-Bromo-4-fluoro-2-nitrobenzene and N-phenylacetamide (81 mg, 0.6 mmol) as starting materials to yield the title compound as brown solid (69 mg, 61%). 1H NMR (DMSO) δ 2.49 (s, 3 H), 7.17-7.32 (m, 2 H), 7.61-7.73 (m, 6 H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[CH:12]=[N:11][CH:10]=[C:9]([Cl:13])[N:8]=1.[NH3:17]>>[F:1][C:2]([F:16])([F:15])[CH2:3][N:4]=[C:5]([NH2:17])[NH:6][C:7]1[CH:12]=[N:11][CH:10]=[C:9]([Cl:13])[N:8]=1
Reactant: FC(F)(F)CNC(=S)Nc1cncc(Cl)n1
Reactant: N
Product: NC(=NCC(F)(F)F)Nc1cncc(Cl)n1
Temperature: 25 °C

Procedure:
To a solution of 2-[3-(2,2,2-trifluoroethyl)thioureido]-6-chloropyrazine (0.7 g.) in alcoholic ammonia (35 ml.) was added red mercuric oxide (0.65 g.) with stirring at room temperature. After stirring overnight, the black mixture was filtered and the black solid washed with alcohol. The resulting yellow filtrate was evaporated to give a yellow solid (0.7 g.). Recrystallisation from hot toluene diluted with petroleum ether (b.p. 60°-80°) yielded colourless needles (0.5 g.) of 2-[2-(2,2,2-trifluoroethyl)guanidino]-6-chloropyrazine m.p. 139°-140°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl[C:11]1[N:16]=[C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:14]=[C:13]([N:23]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[N:25]=[C:24]2[CH:32]([F:34])[F:33])[N:12]=1.COCCOCCN(CCOCCOC)CCOCCOC>O.O1CCOCC1>[F:34][CH:32]([F:33])[C:24]1[N:23]([C:13]2[N:14]=[C:15]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[N:16]=[C:11]([O:1][C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[N:12]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=1
Reactant: Oc1cccnc1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: FC(F)c1nc2ccccc2n1-c1nc(Oc2cccnc2)nc(N2CCOCC2)n1
Yield: 11.9 %

Procedure:
A mixture of 0.301 g (3.16 mmol) of 3-hydroxypyridine and 0.132 g (3.30 mmol) of NaOH was stirred in water until a clear solution was obtained. The water was removed and the residue was combined with a mixture of 0.301 g (3.16 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole and 0.02 g (0.06 mmol) of tris[2-(2-methoxyethoxy)ethyl]amine (TDA-1) in dioxane (12 mL). The resulting mixture was heated under reflux for 2 hr before being cooled, and diluted with water. The resulting precipitate was collected by filtration, and recrystallized from methanol to give 0.160 g (50% yield) of 2-(difluoromethyl)-1-[4-(4-morpholinyl)-6-(3-pyridinyloxy)-1,3,5-triazin-2-yl]-1H-benzimidazole: mp 229-231° C.; 1H NMR (CDCl3) δ8.63-8.60 (m, 2H), 8.12 (dd, J=7.1, 1.4 Hz, 1H), 7.87 (dd, J=7.1, 1.4 Hz, 1H), 7.59 (ddd, J=8.3, 2.7, 1.4 Hz, 1H), 7.45 (ddd, J=8.2, 4.6, 0.3 Hz, 1H), 7.41-7.34 (m, 2H), 7.25 (t, JHF=53.6 Hz, 1H), 3.99-3.96 (m, 2H), 3.89-3.83 (m, 4H), 3.79-3.77 (m, 2H); Anal. Calcd. for C20H17F2N7O2 0.7H2O: C, 54.8; H, 4.2; N, 22.4. Found: C, 54.5; H, 4.0; N, 22.0%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH:11]=O.[NH2:13][C:14]1[CH:15]=[C:16]([CH3:21])[CH:17]=[CH:18][C:19]=1[NH2:20]>C1(C)C=CC=CC=1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]1[NH:20][C:19]2[CH:18]=[CH:17][C:16]([CH3:21])=[CH:15][C:14]=2[N:13]=1
Reactant: Cc1ccc(N)c(N)c1
Reactant: O=Cc1n[nH]c2ccc(Cl)cc12
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc2[nH]c(-c3n[nH]c4ccc(Cl)cc34)nc2c1
Temperature: 100 °C

Procedure:
A flask was charged with 5-chloro-1H-indazole-3-carbaldehyde (1.0 equivalent) and 3,4-diaminotoluene (1.0 equivalent) in toluene and ethanol (approximately 3:1). The flask was heated to 100° C. for 18 hours. The solvent was evaporated, and the residue purified by reverse phase HPLC to provide the desired product as a white solid. LC/MS (m/z) 283.1 (MH+), Rt 2.5 minutes.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7](CC2C=CC(OC)=CC=2OC)[CH2:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:10]=2)=[O:5])[CH3:2].S(Cl)(Cl)=O.C(O)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(O)c2ccc(Oc3ccccc3)cc2CN1Cc1ccc(OC)cc1OC
Solvent: CCO
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 78.9 %

Procedure:
365 mg of 2-(2,4-dimethoxy-benzyl)-4-hydroxy-7-phenoxy-1,2-dihydro-isoquinoline-3-carboxylic acid ethyl ester was dissolved in 7.9 ml of dichloromethane. To the solution was added 92 μL of thionyl chloride. The reaction was stirred at room temperature for 6.5 h, and then 500 μL of ethanol was added and the reaction stirred for an additional 10 min. The mixture was partitioned between ethyl acetate and sodium bicarbonate. The organic fraction was successively washed with 0.5 M HCl, water, brine; dried over anhydrous sodium sulfate, and concentrated to 468 mg of a yellow oil. The oil was purified by flash chromatography on silica gel, eluting with a gradient of 15-50% ethyl acetate in hexanes, to produce 232 mg of crude product, which was crystallized from ether and hexanes to give 193 mg of off-white solid; MS (+) m/z 310.08 (m+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:26])[CH:12]([C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:6][CH:5]=1.C(N(CC)C(C)C)(C)C.Cl.[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[N:41][CH:40]=1>O1CCCC1>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:26])[CH:12]([C:19]2[CH:20]=[CH:21][C:22]([NH:25][C:38]([C:39]3[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=3)=[O:45])=[CH:23][CH:24]=2)[CH2:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(N)cc2)nc1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(NC(=O)c3cccnc3)cc2)nc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 72.6 %

Procedure:
A solution of 6-[2-(4-amino-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid methyl ester (236.1 mg, 0.65 mmol) in tetrahydrofuran (15 mL) at 25° C. was treated with N,N-diisopropylethylamine (0.27 mL, 1.54 mmol) and nicotinoyl chloride hydrochloride (115 mg, 0.64 mmol). The reaction mixture was stirred at 25° C. for 48 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 ethyl acetate/hexanes) afforded 6-(3-cyclopentyl-2-{4-[(pyridine-3-carbonyl)-amino]phenyl}-propionylamino)-nicotinic acid methyl ester (219.6 mg, 72.3%) as a white solid: mp 110-1 15° C.; EI-HRMS m/e calcd for C27H28N4O4 (M+) 472.2110, found 472.2109.
Reaction SMILES: [Si:1]([C:8]#[CH:9])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].FC(F)(F)S(O[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][C:17]=1[Cl:28])(=O)=O.C(N(CC)CC)C>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[C:4]([Si:1]([C:8]#[C:9][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][C:17]=1[Cl:28])([CH3:3])[CH3:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: C#C[Si](C)(C)C(C)(C)C
Reactant: O=S(=O)(Oc1ccc(-c2ccccc2)cc1Cl)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)C#Cc1ccc(-c2ccccc2)cc1Cl

Procedure:
0.84 g (1.2 mmol) of bis-(triphenylphosphine)palladium (II) chloride, 0.23 g (1.2 mmol) of copper (I) iodide, and 6.28 mL (33.6 mmol) of (tert-butyldimethylsilyl)acetylene is added under an argon atmosphere to a solution of 8.1 g (24 mmol) of 3-chlorobiphenyl-4-yl trifluoromethanesulfonate in 50 mL of absolute DMF and 13.31 mL (96 mmol) of triethylamine.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][NH:2]1.[N:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)=[C:15]=[O:16]>CN(C)C=O.ClCCl>[F:24][C:23]([F:25])([F:26])[C:19]1[CH:18]=[C:17]([NH:14][C:15]([N:2]2[CH2:3][CH2:4][C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[NH:12][C:13]=3[CH2:1]2)=[O:16])[CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(C(F)(F)F)c1)N1CCc2c([nH]c3ccccc23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.7 %

Procedure:
A solution of 2,3,4,9-tetrahydro-1H-β-carboline (172 mg) in dimethylformamide (5 mL) was added by a solution of 1-isocyanato-3-(trifluoromethyl)benzene (173 mg) in dichloromethane (5 mL) and stirred overnight at the room temperature. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=6:1) to give the title compound (205 mg) having the following physical data.